Tissue Development, Repair, and Remodeling - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 689

perfusion defects such as heart failure arising from ischemic and non-ischemic
cardiomyopathies.
Pluripotent stem cells such as embryonic stem cells (ESC) can differentiate into
all cell types. Ethical, legal, and biological issues limit their use.
Reprogrammation of adult somatic cells into induced pluripotent stem cells or
induced specialized cells such as cardiomyocytes yields an alternative. However,
further investigations are required. Adult stem cells are most often only able to
form their tissue of origin. In any case, therapy benefits depend on an efficient
engraftment of administered stem cells, proper differentiation, and interaction with
host cells.
Adult multipotent precursors offer alternatives to embryonic stem cells if they
have the same potential. Stem cell function can be enhanced by suitable drugs and
growth factors that promote cell growth, differentiation, survival, and homing.
Bone marrow accomodates various types of stem and precursor cells. They
yield a pro-angiogenic microenvironment. Bone marrow-derived mesenchymal
stem cells (bmMSC) can differentiate into multinucleated myotubes and exhibit
cardiomyocyte-specific gene expression [ 1404 ].
Umbilical cord blood contains a wide variety of stem cells, such as hematopoi-
etic, mesenchymal, and unrestricted somatic stem cells, that can generate numerous
cell types.
Reprogramming of fibroblasts, B lymphocytes, hepatocytes, and gastric epithe-
lial cells to induced pluripotent cells was carried out using retrovirus-mediated
transduction of a defined set of transcription factors in mice (octamer-binding
transcription factor Oct4, SRY-related HMG box Sox2, Kr uppel-like factor KLF4,
and MyC). Functionally redundant KLF2 and KLF5 can replace KLF4 in fibroblast
reprogramming [ 1405 ]. In addition, nuclear receptor ERR (NR3b2) that forms a

complex with Nanog and Oct4 and targets many genes involved in self-renewal and
pluripotency in stem cells participates with Oct4 and Sox2 to conversion of mouse
embryonic fibroblasts to induced pluripotent cells. Nuclear receptor NR3b2 can
replace KLF4 in the presence of Oct4 and Sox2 and in the absence of MyC [ 1405 ].
Embryonic or induced pluripotent stem cells are most often suitable to generate
given cell lineages, but have little or no capacity to commit into other cell lineages.
Multipotent cardiovascular progenitors can enter cardiovascular cell lineages to
give birth to distinct vascular cells. They must not only differentiate into multiple
cell types (arterial, capillary, and venous endothelial and smooth muscle cells,
nodal cells, and atrial and ventricular myocytes) according to types of stimulated
pathways, but also keep the adequate proportion of involved cell types as well
as tissue architecture. Cardiovascular master stem cell is a common multipotent
progenitor that is characterized by cardiac signature gene NKx2-5.
Growth factor-mobilized peripheral blood mononuclear cells represent a suitable
source of autologous progenitor cells when proper differentiation can be achieved.
Activators of early cardiac lineage-restricted gene NKx2-5 include small sulfonyl
hydrazones that can trigger expression of cardiac markers (e.g., transcription

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